Cell growth is the fundamental biological process whereby cells accumulate mass and is an important determinant of the sizes of cells, organs, and organisms (Conlon, I. and Raff, M. (1999), Cell 96, 235–44; Dixon, D. and Fordham-Skelton, T. (1998), Curr. Opin. Plant Biol. 1, 1; Gomer, R. H. (2001), Nat. Rev. Mol. Cell Biol. 2, 48–54; Johnston, L. A. and Gallant, P. (2002), Bioessays 24, 54–64; Stocker, H. and Hafen, E. (2000), Curr. Opin. Genet. Dev. 10, 529–35). The mTOR pathway, along with the PI-3Kinase/PKB/PTEN axis, is emerging as a critical regulator of growth in mammals in response to nutrients, hormones and growth factors (Gingras, A. C., et al., (2001), Genes Dev. 15, 807–26; Kozma, S. C. and Thomas, G. (2002), Bioessays 24, 65–71; Schmelzle, T. and Hall M. N. (2000), Cell 103, 253–62). The central component of the pathway, mTOR (also known as RAFT1 or FRAP), was discovered during studies into the mechanism of action of rapamycin (Brown, E. J., et al. (1994), Nature 369, 756–758; Sabatini, D. M., et al. (1994), Cell 78, 35–43; Sabers, C. J., et al. (1995), J. Biol. Chem. 270, 815–822), an anti-proliferative drug with valuable immunosuppressive and anti-cancer clinical applications (Saunders, R. N., et al. (2001), Kidney Int. 59, 3–16; Vogt, P. K. (2001), Trends Mol. Med. 7, 482–4). mTOR is a member of the PIK-related family of large protein kinases (Keith, C. T. and Schreiber, S. L. (1995), Science 270, 50–1) and mediates the phosphorylation of at least two regulators of protein synthesis and cell growth: S6 Kinase 1 (S6K1) and an inhibitor of translation initiation, the eIF-4E binding protein 1 (4E-BP1) (Brunn, G. J., et al. (1997), Science 277, 99–101; Burnett, P. E., et al. (1998), PNAS 95, 1432–1437; Isotani, S., et al. (1999), J. Biol. Chem. 274, 34493–8). Recent work suggests that deregulation of the mTOR pathway plays a role in the pathogenesis of human disease, as the pathway is constitutively active in tuberous sclerosis (Goncharova, E. A. (2002), J. Biol. Chem. 277, 30958–67; Kwiatkowski, D. J., et al. (2002), Hum. Mol. Genset 11, 525–34), a tumor-prone syndrome caused by mutations in the TSC1 (van Slegtenhorst, M., et al. (1997), Science 277, 805–8) or TSC2 (Consortium, T. E. C. T. S. (1993), Cell 75, 1305–15) genes. Exactly how the mTOR, TSC1/2 and PI-3K/Akt/PTEN pathways interconnect is unknown, but it is likely that these systems integrate growth factor- and nutrient-derived signals to determine overall growth rates. The mTOR pathway is particularly sensitive to the levels of nutrients, such as amino acids (Hara, K., et al. (1998), J. Biol. Chem. 273, 14484–94) and glucose (Dennis, P. B., et al. (2001), Science 294, 1102–5; Kim, D. H., et al. (2002), Cell 110, 163–75), but the molecular mechanisms by which nutrients regulate mTOR are to be understood.
It would be helpful to have methods and compositions that regulate the mTOR pathway, which would be useful as therapeutic approaches for diseases such as cancer, diabetes, and cardiovascular diseases.